Method and device utilizing insulin delivery protocols

ABSTRACT

A method of infusing liquid medicaments including insulin via an insulin pump, includes identifying an insulin delivery protocol associated with ingestion of carbohydrates wherein the insulin delivery protocol is likely to lead to a postprandial drop in blood glucose to a level below a basal level, then proposing at least one alternative insulin delivery protocol to inhibit the postprandial drop in blood glucose by delivering a metered amount of insulin that is appropriate to facilitate the metabolism of the carbohydrates without the postprandial blood glucose level drop. The invention further includes querying the patient as to whether to apply the alternative insulin delivery protocol, receiving instructions from the patient in response to the query, and applying the alternative insulin delivery protocol following receiving instructions from the patient to apply the alternative insulin delivery protocol.

FIELD OF THE INVENTION

The invention relates generally to insulin pumps that are utilized forcontrolled infusion of insulin into the human body. Insulin pumps mayalso include dual hormone therapy devices that infuse insulin andanother hormone or medication into the body. More particularly, theinvention relates to profiles that are used to control the infusion ofinsulin and other medicaments in the treatment of diabetes.

BACKGROUND OF THE INVENTION

There are many applications in academic, industrial, and medical fields,as well as others, that may benefit from devices and methods that arecapable of accurately and controllably delivering fluids, includingliquids and gases that have a beneficial effect when administered inknown and controlled quantities. Such devices and methods may beparticularly useful in the medical field where much of the treatmentsfor a large percentage of patients includes the administration of aknown amount of a substance at predetermined intervals.

Insulin-injecting pumps have been developed for the administration ofinsulin for those suffering from both type I and II diabetes. Recentlycontinuous subcutaneous insulin injection and/or infusion therapy hasbeen adapted for the treatment of diabetes. Such therapy may include theregular and/or continuous injection or infusion of insulin into or underthe skin of a person suffering from diabetes and offers an alternativeto multiple daily injections of insulin by an insulin syringe or aninsulin pen.

Generally, present insulin pump therapy is based on the use andapplication of currently available, so-called, “rapid-acting” insulinanalogues, including insulin lispro (marketed by Eli Lily & Companyunder the trademark Humalog®), insulin glulisine (marketed bySanofi-Aventis under the trademark Apidra®), and insulin aspart(marketed by Novo Nordisk under the trademark NovoLog®). More recently,ultra-rapid acting insulins have been developed. Further, other drugshave been developed that either modify insulin action time or alter therate of metabolism of food. These all change the way that post-prandialblood glucose levels behave in a somewhat similar fashion.

Currently, in presently available insulin pumps, an insulin bolus isdelivered as rapidly as it can be. The delivery of an insulin boluscreates an abrupt rise in the level of insulin in the blood stream whichencourages the rapid metabolism of glucose. The beginning of insulinappearance in the blood stream is delayed from the time of infusionbecause of the time required for insulin absorption and distribution inthe circulation. With ultra-rapid acting insulins the delay time is lessthan for fast acting insulin. Thus, the delivery of such an insulinbolus according to a “normal” protocol may cause an excessive metabolismof glucose thereby causing a drop in blood glucose which can bedangerous. In extreme cases, the drop in blood glucose can lead toinsulin shock, which is also known as hypoglycemic shock. In rare caseshypoglycemic shock can even cause death.

The use of pramlintide, (e.g., pramlintide acetate marketed by BristolMyers-Squibb under the trademark Symlin®) is becoming increasinglycommon in the treatment of type I diabetes. Pramlintide is syntheticamylin, an agent that acts to slow the rate of gastric emptying andtherefore the rate at which food is released into the small intestine.Accordingly, this slows the rate at which food is metabolized.Glucagon-like peptide-1 (GLP-1) agonist therapy may also be used to slowthe rate of gastric emptying which in turn slows the rate of absorptionof food in the small intestine. The use of these agents results in aless pronounced rise in blood sugar after eating that also may last fora longer period of time.

The development of new insulins as well as adjunctive medicinal therapyfor diabetes creates a need for new therapy protocols to be used with aninsulin pump or a dual therapy insulin pump.

SUMMARY OF THE INVENTION

The present invention solves many of the above-indicated problems andassists individuals under treatment for diabetes in attaining the goalof as constant a blood sugar level as possible. The maintenance of aconstant blood sugar level is expected to reduce the damaging sequelaeof diabetes mellitus that include microvascular changes in the eyes andelsewhere in the body such as retinopathy, nephropathy and neuropathy aswell cardiovascular disease.

According to the invention, current insulin pump based therapies inwhich a bolus of insulin is delivered as quickly as it can be, thuscreating a rapid rise in insulin level, are modified to accommodate morerapidly acting insulins and complementary drug therapies, such aspramlintide, which cause a similar post-prandial effect by slowing therate at which food is emptied from the stomach and thus the metabolismof carbohydrates. The invention is also useful with modified insulinthat has insulin action time modifiers, such as hyaluronidase, added toit. Further, the invention also is well suited to be used along withinsulin infusion site modifiers. For example, this includes but is notlimited to, products that apply heat to the infusion site. If theinsulin infusion site is heated, the absorption of insulin isfacilitated. Other insulin infusion site modifiers are being developedas well.

In one embodiment, the invention includes a method of providing dualhormone therapy for diabetes in which two hormones are supplied fromseparate compartments in the same insulin pump and a controller isutilized to maintain a memory when pramlintide (or another agent thatslows gastric emptying) has been administered and when it has not.Accordingly, based on this information, the pump can be activated toprovide a standard insulin bolus or to provide an extended or other newtype of insulin bolus as discussed herein. The extent to which a bolusis extended is governed by a new metric not currently used in prior artinsulin pumps.

According to one embodiment of the invention, a ratio comparing minutesof bolus extension to the dose of pramlintide (or other agent) is used.Accordingly, if a sufficiently large amount of carbohydrate is ingestedabove a predetermined threshold, a dose of pramlintide (or other agent)may be given. In this case, a bolus of insulin may be infused along withan insulin bolus extension. According to an embodiment of the invention,the length of the extension is proportional to the dose of pramlintide.According to another embodiment of the invention, an extended bolus maybe given if a dose of pramlintide exceeds a certain predeterminedthreshold.

According to another embodiment of the invention, a bolus whose shapecan be represented in a graph is more similar to a single sine wave or aGaussian distribution to approximate the expected post-prandial rise inblood glucose levels. Current insulin pumps deliver boluses that areeither abrupt and immediate or where a fraction of the bolus isdelivered immediately and a remaining fraction is delivered over anextended period of time. As the speed of insulin action increases it isdesirable for the shape of the insulin infusion profile to more closelymatch the shape of the carbohydrate profile.

According to another embodiment of the invention, a small amount ofinsulin is delivered in a first dose followed by an increased secondamount of insulin delivered following a period of time, again followedby a third decreased amount of insulin delivered.

According to another embodiment of the invention, metrics that are usedare the time to peak bolus and the total bolus extension of time.According to the invention, these two metrics are used to govern theshape of a sine wave like bolus. The goal of therapy under the presentinvention is to provide the required amount of insulin at the right timerelative to blood sugar control so that the blood sugar level may bemaintained at a constant level as possible. Slower food movement intothe small intestine as controlled by pramlintide and related medicationsand the utilization of ultra-rapid acting insulins, as controlled by theinvention, may permit better overall blood sugar control than haspreviously been possible.

The goal of the invention is to match the rate at which food ismetabolized to the rate at which insulin becomes active. A concern withultra-rapid acting insulins is that the insulin may act faster than thefood uptake that causes a rise in blood sugar. Accordingly, there evenmay be a postprandial drop in blood glucose level rather than thenormally expected rise. According to the invention, with the use ofultra-rapid acting insulins, meal boluses are carbohydrates boluses thatmay be extended. According to one embodiment of the invention, the shapeof the extension is similar to a sine wave or Gaussian curve.

According to the invention, with both pramlintide (or other like actingmedicaments) use and ultra-rapid acting insulin use, it is likely that acorrection bolus should be infused immediately. If the patient using thepump promptly enters meal boluses or carbohydrate boluses, thecontroller of the insulin pump can track delivery of a correction or ameal bolus and a particular bolus shape can be suggested to the patient.

According to the invention, even combination boluses where a part of thebolus is for correction and part of the boluses is intended toaccommodate a future meal are calculated and delivered.

Another context in which the invention is applicable is in therapy whereinsulin action time modifiers are included as an adjunct to standardinsulin therapy. For example, it is known that the inclusion ofhyaluronidase to insulin causes the standard insulin to act morerapidly. According to the invention, with the use of insulin action timemodifiers, either mixed directly with the insulin within the sameinjection or separately injected using a dual drug insulin pump. Insulinboluses are modified or extended as described herein.

According to one embodiment of the invention, the amount of extension isbased on a ratio of insulin to the modifier that is injected. Thus, theinvention also includes an additional metric that is used to calculatethe proper insulin dose.

According to embodiments of the invention, the metric is based on aratio of insulin to modifier or may be based on a number of minutes ofbolus extension of insulin per dose of modifier. Thus the period ofextension is proportional to the dose of modifier. According to anotherembodiment of the invention, a combination of the ratio of insulin tomodifier and a period of extension per dose of modifier is used.Further, an alternative insulin delivery protocol may be appropriate ifhyalouronidase or another insulin action modifier has been given oversome predetermined earlier time span. For example, if the modifier hasbeen used by the patient in the last 24 or 48 hours it may beappropriate to use an alternative insulin delivery protocol as describedherein.

Further, if the dual drug pump is utilized, the pump controller cantrack when both drugs are pumped and therefore predict when to apply thecorrection.

Further, according to another embodiment of the invention, if insulinand the modifier are mixed, the mixing ratio is entered into the pumpcontroller so that the pump can calculate how much to extend or modifyboluses.

Rapid changes in blood glucose level can cause patients with diabetes tofeel uncomfortable or emotionally out of balance in ways that patientsfind hard to describe. This can occur when an excessively large insulinbolus is delivered or if the patient engages in exercise with an excessof insulin in his system. With increasing speed of insulin action it maybe desirable to extend even correction boluses to reduce the rate ofchange of blood sugar level. Thus, according to another embodiment, theinvention includes an alternative insulin delivery protocol wherein acorrection bolus is delivered that includes a correction bolus extensionto moderate the rate at which blood glucose change occurs. According toanother embodiment, the invention includes utilizing an alternativeinsulin delivery protocol that maintains the rate of change of bloodglucose below a preselected level.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a front view in perspective of an embodiment of an infusionpump system.

FIG. 1B is a rear view of an infusion cartridge coupled to the infusionpump device of FIG. 1A.

FIG. 1C is a rear schematic view of an interior of the infusion pump andcartridge embodiments of FIG. 1A.

FIG. 1D illustrates a section view of a portion of the infusioncartridge and pump device of FIG. 1A.

FIG. 2 is a section view of a delivery mechanism of an infusion pumpwith the spool of the delivery mechanism positioned at a distal hardstop for filling of the expandable reservoir according to an embodimentof the present invention.

FIG. 3 is a section view of the delivery mechanism embodiment of FIG. 2with the spool of the delivery mechanism positioned for filling of acollapsible volume of the spool.

FIG. 4 is a section view of the delivery mechanism embodiment of FIG. 2with the spool of the delivery mechanism positioned after filling of thecollapsible volume of the spool.

FIG. 5 shows the spool of FIG. 2 with the collapsible volume of thedevice full of fluid being displaced proximally towards the dispenseport of the device.

FIG. 6 is a section view of the delivery mechanism embodiment of FIG. 2with the spool of the delivery mechanism positioned prior to delivery offluid into the dispense port from the collapsible volume of the spool.

FIG. 7 is a section view of the delivery mechanism embodiment of FIG. 2with the spool of the delivery mechanism positioned after delivery offluid from the collapsible volume of the spool into the dispense port.

FIG. 8 is a graph depicting a rise in blood glucose over time thatoccurs after an ingestion of food, particularly an ingestion ofcarbohydrates.

FIG. 9 is a graph depicting a rise in blood glucose over time that isreduced in amplitude and lengthened in time occurs after an ingestion ofcarbohydrates and use of pramlintide or a similar agent.

FIG. 10 is a graph depicting an undesirable postprandial drop in bloodglucose over time that occurs after an ingestion of carbohydrates in thepresence of other circumstances such as infusion of an ultra-rapidacting insulin, use of pramlintide or similar agents.

FIG. 11 is a graph depicting a typical prior art insulin bolus deliverywith a bolus extension.

FIG. 12 is a graph depicting an alternative insulin delivery protocolaccording to an example embodiment of the invention.

FIG. 13 is a graph depicting another alternative insulin deliveryprotocol according to an example embodiment of the invention.

FIG. 14 is a graph depicting another alternative insulin deliveryprotocol having a Gaussian curve-like structure according to an exampleembodiment of the invention.

FIG. 15 is a graph depicting another alternative insulin deliveryprotocol including an initial bolus followed by a Gaussian curve-likeextension according to an example embodiment of the invention.

FIG. 16 is a flowchart depicting methods according to an exampleembodiment of the invention.

DETAILED DESCRIPTION

The invention generally applies to the operation and utilization ofinsulin infusion pumps. Included below is a description of an insulininfusion pump with which the methods of the invention may be used.

Provided herein are systems, devices and methods for identifying aninsulin delivery protocol associated with ingestion of carbohydrateswherein the insulin delivery protocol is likely to lead to apostprandial drop in blood glucose to a level below a basal level thatis likely to deprive a patient of sufficient blood glucose to functionnormally. The invention also includes proposing at least one alternativeinsulin delivery protocol to inhibit the postprandial drop in bloodglucose by delivering a metered amount of insulin that is appropriate tofacilitate the metabolism of the carbohydrates without the postprandialblood glucose drop. The inventions are usable in the context of aninfusion pump and particularly in an insulin pump. Some embodiments mayinclude advances in the internal components, the control circuitry, andimprovements in a user interface of the systems and devices. Theadvances may allow for a safer and more accurate delivery of medicamentto a patient than is currently attainable today from other devices,systems, and methods. Although embodiments described herein may bediscussed in the context of the controlled delivery of insulin, deliveryof other medicaments as well as other applications are alsocontemplated. Device and method embodiments discussed herein may be usedfor pain medication, chemotherapy, iron chelation, immunoglobulintreatment, dextrose or saline IV delivery, or any other suitableindication or application. Non-medical applications are alsocontemplated.

FIGS. 1A-1D shows an embodiment of an infusion pump system 110 includingan infusion cartridge 112 and pump device 114. Infusion cartridge 112can be a reversibly removable and interchangeable element that may beinserted into different pump devices. Referring to FIG. 1A, a front viewof the pump device 114 is shown and includes a user friendly userinterface 116 on a front surface 118 of the pump device 114. The userinterface 116 includes a touch sensitive screen 120 that may beconfigured to display a variety of screens used for displaying data,facilitating data entry by a patient, providing visual tutorials, aswell as other interface features that may be useful to a patientoperating the pump device 114. FIG. 1B is a rear view of the pump device114 and illustrates the detachable installment of the infusion cartridge112 in a slot 122 of the pump device 114 which is configured to acceptthe cartridge 112.

FIG. 1C is a schematic view of an open housing 124 of the pump device114 which shows schematically some components that may be included inembodiments of the pump device 114. The cartridge 112 may include afluid interface configured to receive a fluid such as collapsiblereservoir 126. The collapsible reservoir 126 may be formed from aflexible material or membrane 128 that is disposed about an interiorvolume of the reservoir 126. The cartridge 112 also includes asubstantially rigid container 130 sealed around the flexible material ofthe collapsible reservoir 126. A disposable delivery mechanism 132 isdisposed within the disposable cartridge 112 and may have a fill port134 with a re-sealable septum 136 sealed over the fill port 134, areservoir inlet port 138 in fluid communication with an interior volume140 of the collapsible reservoir 126, a fluid dispense port 142 in fluidcommunication with a bore 144 of the delivery mechanism 132, a ventinlet port 146 and a vent outlet port 148 both in fluid communicationwith the bore 144. The collapsible reservoir 126 may have a bag-likestructure with flexible walls that can collapse and expand dependingupon the amount of material in the volume of the reservoir. The interiorvolume of the reservoir may be in fluid isolation from the remaininginterior volume of the rigid container 130.

The cartridge 112 may be releasably and operatively secured to a housing124 of the pump device 114. The housing 124 may be configured to house adrive mechanism 150 including a motor 152 and gear box 154 disposed inthe housing 124 and detachably coupled to a spool member 156 of thedelivery mechanism 132. At least one pressure sensor 158 may be disposedin a volume 160 between an outside surface 162 of the flexible materialor membrane 128 of the collapsible reservoir 126 and an inside surface164 of the substantially rigid shell or case 130. The graphic userinterface 116 may be operatively coupled to a controller 168, which mayinclude at least one processor 170, a memory device 172 and connectivecircuitry or other data conduits that couple the data generating or datamanaging components of the device. A power storage cell in the form of abattery 174 that may be rechargeable may also be disposed within thehousing 124. Data generating or managing components of the device mayinclude the processor(s) 170, the memory device 172, sensors 158,including any pressure or temperature sensors, the GUI 166 and the like.

The pressure inside the infusion cartridge 112, and particularly thevented volume 160 of the infusion cartridge 112, may be measured by apressure sensor 158 disposed in the infusion cartridge 112 or in thepump device 114 in a volume, such as pocket 186 as shown in FIG. 1D.

Pocket 186 is an interior volume disposed within the pump device 114 andin fluid communication with an interior volume of the fluid cartridge112. The pocket 186 is in sealed relation with the interior volume 160of the cartridge. As such, a pressure sensor 158 disposed within thevolume of the pocket 186 will read the pressure of the volume 160 in thecartridge, but can remain with the pump device 114 after disposal of thedisposable cartridge 112. This configuration lowers the cost of thecartridge while providing the means of pressure measurement within thecartridge 112. In some embodiments, data from the pressure sensor 158may be used to provide a measurement of how much insulin or othermedicament is being delivered by the first pump device 114.Alternatively, the pressure sensor 158 can be disposed within thecartridge directly in the vented volume 160.

The pump device 114 can also include a thermistor or other temperaturesensor 188 including an optical or infrared sensor that measures thetemperature of the insulin or other medicament within the reservoir 126upon coupling the infusion cartridge 112 with the pump device 114.Taking the temperature of the air may be important in measuring how muchinsulin or other medicament is in the fluid reservoir. In someembodiments, the thermistor or other temperature sensor 188 ispositioned in the pocket 186 such that it can measure the temperature ofthe air in the pocket 186 as shown in FIG. 1D. As noted above, thepocket 186 may also include a pressure sensor 158 coupled to thecontroller 168 for measuring pressure within the pocket 186 and volume160. Because the air in the pocket 186 is in fluid communication withthe residual air within the chamber 160, the temperature and pressure ofthe air in the infusion cartridge 112 surrounding the fluid reservoir126 may be equal or approximately equal to the temperature and pressureof the air in contact with the temperature sensor 188 and pressuresensor 158. In turn, the temperature sensor 188 may provide a relativelyaccurate measurement of the temperature of the insulin or othermedicament within the reservoir 126.

Referring to FIGS. 2-7, an embodiment of the delivery mechanism 132 isshown in a fluid delivery cycle sequence wherein fluid from the interiorvolume of the reservoir 126 is drawn into the bore 220 of the deliverymechanism 132 and dispensed from the dispense outlet port 142.

Referring again to FIG. 2, a portion of the fluid reservoir cartridge112 including a delivery mechanism 132 is shown in section as well as aportion of a drive mechanism 150 of an infusion pump. The disposablefluid cartridge 112 includes the delivery mechanism 132 which has adelivery mechanism body 236 and a bore 220 disposed in the deliverymechanism body 236. The bore 220, which may have a substantially roundtransverse cross section, includes a distal end 238, a proximal end 240disposed towards the drive mechanism 150 of the infusion pump 114, aninterior volume 242, a reservoir inlet port 138, a fluid dispense port142, a vent inlet port 146 and a vent outlet port 148. The spool 156,which may also have a substantially round transverse cross section, isslidingly disposed within the bore 220 and forms a collapsible firstvolume 244 and a vent second volume 246 between the bore 220 and anoutside surface 266 of the spool 156.

The collapsible first volume 244 of the delivery mechanism 132 may bepositionable to overlap the reservoir inlet port 138 independent of anoverlap of the fluid dispense port 142. The collapsible first volume 244may be formed between a first seal 248 around the spool 156, a secondseal 250 around the spool, an outer surface of the spool body betweenthe first and second seal 250 and an interior surface 252 of the bore220 between the first and second seal 248 and 250. The first and secondseals 248 and 250 are axially moveable relative to each other so as toincrease a volume of the collapsible volume 244 when the first andsecond seals 248 and 250 are moved away from each other and decrease thecollapsible volume 244 when the seals 248 and 250 are moved closertogether.

The second seal 250 is disposed on a main section 254 of the spool 156of the delivery mechanism 132 and moves in conjunction with movement ofthe rest of the spool. A proximal end 196 of the spool 156 is coupled toa ball portion 194 of a drive shaft 190 of the drive mechanism 150 ofthe pump device 114. The drive mechanism 150 includes a rack and pinion192 mechanism actuated by an electric motor 152 through a gear box 154.As such, the second seal 250 moves or translates axially in step withaxial translation of the spool 156 and drive shaft 190. The first seal248, however, is disposed on a distal section 258 of the spool 156 whichis axially displaceable with respect to the main section 254 of thespool 156. The distal section of the spool 156 is coupled to the mainsection of the spool by an axial extension 260 that is mechanicallycaptured by a cavity 261 in the main section 254 of the spool 156. Thisconfiguration allows a predetermined amount of relative free axialmovement between the distal section 258 of the spool and the nominalmain section 254 of the spool 156.

For some embodiments, a volume of a “bucket” of fluid dispensed by acomplete and full dispense cycle of the spool 156 may be approximatelyequal to the cross section area of the bore 220 multiplied by the lengthof displacement of the captured axial extension of the spool 156 for thedistal section 258. The complete bucket of fluid may also be dispensedin smaller sub-volumes in increments as small as a resolution of thedrive mechanism 150 allows. For some embodiments, a dispense volume orbucket defined by the complete collapsible volume 244 of the deliverymechanism 132 may be divided into about 10 to about 100 sub-volumes tobe delivered or dispensed. In some cases, the maximum axial displacementbetween the distal section and main section of the spool may be about0.01 inch to about 0.04 inch, more specifically, about 0.018 inch, toabout 0.022 inch.

In use, once the reservoir cartridge 112 of the infusion pump system 110has been installed or otherwise snapped into place in the slot 122 ofthe pump device 114, the interior volume 140 of the collapsiblereservoir 126 may then be filled with a desired fluid 121 fordispensing. In order to fill the reservoir 126, the spool 156 may betranslated by the drive mechanism 150 to a hard stop position 226 asshown in FIG. 2. In the hard stop position 226 the first seal 248 isdisposed proximally of a relief port 310, the relief port 310 beingdisposed in fluid communication between a distal end 238 of the bore 220and the reservoir volume 140. In the hard stop position, the first seal248 is also disposed distally of the reservoir inlet port 138. In thehard stop position, a distal end 316 of the spool 156 is contacting thedistal end 238 of the bore 220 or a shoulder portion 312 of the distalend 238 of the bore 220 to prevent any further distal displacement ofthe spool 156.

A reservoir fill port 134 is disposed on a top portion of the bore 220substantially opposite the bore 220 of the reservoir inlet port 138.With the spool 156 and seals 248, 250, 262 and 264 thereof sopositioned, a patient may then obtain an amount of a desired fluid to bedispensed. In some cases, if the desired fluid to be dispensed isinsulin or other suitable medicament, the patient 127 typically storesthe insulin in a refrigerated glass container. The insulin is thenaccessed with a hypodermic needle 222 of a syringe device and drawn intoan interior volume of the syringe (not shown). The tip of the hypodermicneedle 222 of the syringe may then be pushed through a septum membrane136 that seals the reservoir fill port 134 as shown and fluid manuallydispensed from the interior volume of the syringe, through thehypodermic needle 222, through a bubble trap volume 314 in the bore 220of the delivery mechanism 132 and into the interior volume 140 of thecollapsible reservoir 126 of the cartridge 112 as shown by the arrow 318in FIG. 2.

As discussed above with regard to other embodiments of the deliverymechanism 132, the vented volume 160 of the cartridge 112 disposedbetween an outside surface 162 of the flexible membrane 128 of thecollapsible reservoir 126 and an inside surface 164 of the rigid shell130 may include or be in operative communication with a pressure sensor158. The pressure sensor 158 may be used to monitor the pressure withinthe vented volume 160 during the filling of the collapsible reservoir126. The controller 168 of the pump system 114 may be programmed withinformation regarding the fixed volume of the rigid shell 130 of thecartridge 112 and configured to calculate the volume of fluid loadedinto the collapsible reservoir 126 based on the pressure rise within therigid shell 130 upon filling of the collapsible reservoir 126. The dataregarding the volume of fluid loaded into the collapsible reservoir 126may be stored and used to calculate and display data later in the usecycle such as fluid remaining in the collapsible reservoir 126 and thelike.

Once the collapsible reservoir 126 contains a desired amount of a fluid121 to be dispensed, a dispense cycle may be initiated by driving thespool 156 with the drive mechanism 150 based on commands from acontroller 168 of the pump device to a position with the collapsiblefirst volume 244 in communication with the reservoir inlet port 138. Thehard stop position shown in FIG. 2 is such a position. If the spool 156has been driven to this hard stop position 226 in a distal directionfrom previous proximal position, the friction generated between thefirst seal 248 of the spool 156 and the inside surface 252 of the bore220 will have collapsed the collapsible volume 244 of the deliverymechanism 132 with the first seal 248 and second seal 250 in a leastaxially separated state. In this state, the collapsible volume 244 has aminimum volume. Such a state of the delivery mechanism 132 is shown inFIG. 2. Once in this pre-fill position, the spool 156 may then be drivenso as to axially separate the first and second seals 248 and 250 (andthe main section 254 of the spool 156 and distal section 258 of thespool 156) of the collapsible first volume 244 and draw fluid into thefirst volume 244 through the reservoir inlet port 138 from the reservoir126 as shown by the arrow 320 in FIG. 3. As the fluid 121 is drawn intothe collapsible volume 244, the pressure within the vented volume 160decreases. As previously discussed, this drop in pressure may be used inaccordance with the ideal gas law to determine the amount of materialtaken from the collapsible reservoir 126. An unexpected reading based onthe magnitude of the translation of the main section 254 of the spool156 may also be used to detect a failure of a portion of the deliverymechanism 132 in some cases.

The collapsible volume 244 of the delivery mechanism 132 may becompletely filled by proximally retracting the main section 254 andsecond seal 250 of the spool 156 relative to the first seal 248 anddistal section 258 of the spool 156 as shown by arrow 322 on spool 156in FIG. 4. Once filled, the spool 156 may then be driven in a proximaldirection as shown in FIG. 5 wherein there are two seals 248 and 250disposed in the bore 220 between the reservoir inlet port 138 and reliefport 310 and the dispense port 142. As shown by arrow 323 and arrow 324in FIG. 5, both the main section 254 and distal section 258 of the spool156 are proximally retracted together. The captured axial extension ofthe distal section 258 by the main section 254 pulls the distal sectionalong without axial displacement between the main section 254 and distalsection 258 of the spool 156 The dispense port may be in fluidcommunication with a subcutaneous portion of a patient's body. Thedelivery mechanism 132 always includes at least one seal 248 or 250disposed in the bore 220 between the reservoir volume 140 and material121 disposed therein and the dispense port 142 in order to prevent afree flow condition wherein the material 121 in the reservoir 126 is inuninterrupted communication with the patient's body.

Once filled, the spool 156 and filled collapsible volume 244 may beproximally displaced with the drive mechanism 150 to a position with thecollapsible first volume 244 in communication with the fluid dispenseport 142 of the bore 220 as shown in FIG. 6. Once the spool 156 ispositioned as shown in FIG. 6, the main section of the spool 156 maythen be axially driven in a distal direction by the drive mechanism 150with the distal section 258 of the spool remaining stationary orsubstantially stationary. This axial distal movement of the main section254 as indicated by arrow 326 on the spool 156 shown in FIG. 7, servesto at least partially collapse the collapsible first volume 244.Collapsing the first volume 244 of the delivery mechanism 132 dispensesfluid from the collapsible first volume 244 through the fluid dispenseport 142 as shown by the arrow 328 in FIG. 7. Once all fluid from thecollapsible first volume 244 is dispensed in this manner, additionalcycles as described above can be completed to provide additional insulinto the patient. Further details on the operation and configuration ofsuch an infusion pump can be found in U.S. Pat. No. 8,287,495, which ishereby incorporated by reference herein in its entirety.

FIG. 8 is a graph schematically depicting a rise in blood glucose overtime that occurs after ingestion of food; particularly, ingestion ofcarbohydrates. The rise in blood glucose occurs in people suffering fromdiabetes because of insufficient insulin production or production ofinsulin that is ineffectively used. This at least partially uncontrolledrise in blood glucose is a contributor to the sequelae of diabetes thatinclude microvascular changes in the eyes and elsewhere in the body.Complications of diabetes include retinopathy, nephropathy andneuropathy as well as cardiovascular disease.

According to the invention, current insulin pump therapies in which abolus of insulin is typically delivered abruptly and quickly, thuscreating a rapid rise in insulin level, are modified to provide moreeffective blood sugar modulation—particularly in the case of the use ofrapid-acting insulins and complementary drug therapies.

FIG. 9 is a graph schematically depicting a more gradual rise in bloodglucose over time, with the blood glucose level having a reducedamplitude and a lengthened time course as compared to FIG. 8. This sortof postprandial rise in blood sugar occurs, for example, when gastricemptying is slowed. This occurs, for example, when a medication such aspramlintide or a GLP-1 agonist is used. Because gastric emptying isslowed, the absorption of food is slowed and the rise in blood sugar isin turn more gradual and has a lower peak amplitude over time.

FIG. 10 is a graph schematically depicting an undesirable postprandialdrop in blood glucose over time that can occur under certaincircumstances that are addressed by embodiments of this invention. Thisatypical drop in blood glucose can occur, e.g., after an ingestion ofcarbohydrates in the presence of other circumstances.

Circumstances that can cause a postprandial drop in blood glucoseinclude infusion of ultra-rapid-acting insulin, where the action of theinsulin is faster than the expected rise in blood sugar. Thus, insulinis metabolized more quickly than are carbohydrates, and an undesirabledrop in blood glucose may occur. Having an undesirable drop in bloodglucose can lead to a circumstance where insufficient blood glucose isavailable for nutrition and can lead to problems. Such problems caninclude in extreme cases, insulin shock which can cause serious harm orin rare cases even death. Neuroglycopenia is another concern that canarise when blood glucose level drops to a level below that needed fornormal physiological function. Neuroglycopenia occurs when the braindoes not receive sufficient glucose to support brain metabolism and tofunction properly. Neuroglycopenia can present with a wide variety ofneurological symptoms including confusion, ataxia, fatigue, anxiety,moodiness and depression.

Another circumstance that can cause an undesirable postprandial drop inblood glucose is the use of pramlintide or a GLP-1 agonist incombination with insulin therapy. If the rise in blood glucose has beenmodified as in FIG. 9, a conventionally-used bolus of insulin may causean undesirable quick metabolism of blood glucose, thus resulting in theaforementioned postprandial drop in blood glucose.

Thus, with the benefit of the invention and the embodiments discussedherein, it is expected that blood glucose can be maintained at arelatively constant level without an undesirable postprandial drop inblood glucose.

FIG. 11 is a graph schematically depicting a typical prior art insulinbolus delivery profile, with a bolus extension, as a function of time.As can be seen, a bolus of insulin may be delivered quickly, causing arelatively large quantity of insulin to be infused and to be present inthe blood stream relatively rapidly in anticipation of a blood glucoserise that would otherwise occur with ingestion of carbohydrates. Thebolus extension is intended to cover the metabolism of insulin over timeafter the initial rise in blood glucose that would already occur.

Referring now to FIG. 12, an alternative insulin delivery protocolaccording to an example embodiment of the invention is depicted inschematic form as a function of time. According to this exampleembodiment of the invention, insulin is delivered at a basal level 400,followed by a first small bolus 402, followed by a larger bolus 404 andthen a second small bolus 406. After second small bolus 406, insulindelivery returns to the basal level 400. As can be seen, this deliveryof insulin more closely aligns with the expected rise in blood glucoseas depicted in FIG. 8. Accordingly, an insulin delivery protocolaccording to this embodiment of the invention is well suited to maintainblood glucose at a more constant level.

Referring now to FIG. 13, another insulin delivery protocol 408 isdepicted in schematic form as a function of time. According to thisembodiment of the invention, insulin is maintained at a basal level 400followed by first small bolus 410. This is then followed by first restperiod 412 in which insulin delivery returns to a basal level 400. Thisis then followed by a larger bolus 414 which in turn is followed bysecond rest period 416 during which insulin delivery returns to a basallevel 400. Finally, a second small bolus 418 is delivered followed by areturn to basal level 400. Again, it is expected in the circumstance ofa blood sugar rise similar to that depicted in FIG. 8, a more constantblood glucose level would be maintained within this delivery protocolthan prior art delivery protocols. The relative heights of the differentinsulin delivery levels in FIGS. 12 and 13 are for example only. Thoseof ordinary skill in the art can adjust the size of the bolus deliveriesin order to accommodate an expected blood glucose rise.

Referring now to FIG. 14, another insulin delivery protocol 426 isdepicted in schematic form as a function of time. As can be seen byexamination of FIG. 14, in insulin delivery protocol 426 aGaussian-shaped insulin bolus 428 is delivered. In other words, thedelivery of insulin approximates a Gaussian curve. It should beunderstood that the insulin delivery in this protocol 426 does notnecessarily have to be in the form of an exact Gaussian curve asmathematically defined; rather, it approximates a Gaussian curve in thatthere is a gradual rise in insulin delivery to a peak followed by agradual decline in insulin delivery as time progresses. This curve isexpected to approximate the expected rise in blood glucose over time asdepicted in FIG. 8 and thus is expected to provide a relatively constantlevel of blood glucose over the time of insulin delivery. Gaussianinsulin bolus 428 may also have a lower peak in order to accommodate anexpected blood glucose rise similar to that depicted in FIG. 9.

FIG. 15 depicts another insulin delivery protocol 460 in schematic formas a function of time, including insulin bolus 432 and Gaussianextension 434. According to this embodiment of the invention, an initialinsulin bolus 432 is delivered followed by an extension that is notconstant in insulin delivery but that gradually rises and falls overtime, approximating a Gaussian curve. As discussed above, this is notintended to describe a curve that is precisely mathematically Gaussianin structure but a curve that gradually rises and then gradually falls.The curve may be, but need not be, generally symmetrical.

Referring now to FIG. 16, a flow chart depicting a method according tothe invention is depicted. This method may be implemented in theoperation of an insulin pump that includes a controller such as thatdescribed herein.

A method according to the invention for infusing liquid medicamentsincluding insulin, via an insulin pump having at least one reservoircontaining the liquid medicaments includes identifying an insulindelivery protocol associated with ingestion of carbohydrates wherein theinsulin delivery protocol is likely to lead to a postprandial drop inblood glucose to a level below a basal level that is likely to deprive apatient of sufficient blood glucose to function normally 436. The methodmay further include proposing at least one alternative insulin deliveryprotocol to inhibit the postprandial drop in blood glucose by deliveringa metered amount of insulin that is appropriate to facilitate themetabolism of the carbohydrates without the postprandial blood glucosedrop 438. The method may further include querying the patient as towhether to apply the alternative insulin delivery protocol 440 andreceiving instructions from the patient in response to the query 442 andapplying the alternative insulin delivery protocol following receivinginstructions from the patient to apply the alternative insulin deliveryprotocol 444.

According to another embodiment of the invention, the invention mayinclude delivering a first bolus of the liquid medicament having a firstvolume at a time t1 446, delivering a second bolus of the liquidmedicament having a second volume at a time t2 448 and delivering athird bolus of the liquid medicament having a third volume at a time t3440.

According to another embodiment of the invention, the invention mayfurther include delivering an initial bolus followed by a bolusextension, the bolus extension rising and falling in volume in acyclical wave fashion over a period of time 452.

According to another example embodiment of the invention, the method mayinclude delivering insulin over an extended period of time during whichthe volume of insulin delivered rises and falls in a cyclical wavefashion over a period of time and then declines to a basal level 454.

According to another example embodiment of the invention, the methodfurther includes delivering a volume of insulin at a volume rate basedon the expected postprandial rise in blood glucose that mirrors theexpected postprandial rise in blood glucose whereby blood glucose ismetabolized such that blood glucose level is maintained to besubstantially constant following the ingestion of carbohydrates 456.

According to another example embodiment of the invention, the methodfurther includes delivering a volume of insulin at a volume rate basedon the expected postprandial rise in blood glucose that mirrors theexpected postprandial rise in blood glucose such that the volume rate ofinfusion generally resembles a Gaussian curve 458.

According to another embodiment of the invention, the method may includeidentifying the use of a dose of an agent that slows gastric emptying asa factor that is likely to lead to a postprandial drop in blood glucoseto a level below a basal level that is likely to deprive a patent ofsufficient blood glucose to function normally 460.

According to another embodiment of the invention, the method may includeconforming the volume rate of infusion to generally resemble theGaussian curve that is flattened to conform with the slowed gastricemptying 462.

According to another example embodiment, the method may includeselecting the agent from a group of agents consisting of pramlintide,GLP-1 agonists and combinations thereof 464.

According to another embodiment of the invention, the method may includedelivering an initial bolus of insulin followed by a bolus extension,the bolus extension being delivered over a period of time that isdirectly proportional to the dose of the agent that slows gastricemptying 468.

According to another embodiment of the invention, the method may includereceiving an input from the patient that the patient has ingested or isabout to ingest a quantity of carbohydrate and an input from the patientenumerating the quantity of carbohydrate; and applying the alternativeinsulin delivery protocol only if the enumerated quantity ofcarbohydrate exceeds a predetermined threshold 470.

According to another embodiment of the invention, the method furtherincludes delivering the dose of the agent that slows gastric emptyingvia a dual hormone therapy device 472.

According to another embodiment of the invention, the method may includeidentifying use of an insulin action time modifier as a factor that islikely to lead to the postprandial drop in blood glucose to a levelbelow a basal level that is likely to deprive the patient of sufficientblood glucose to function normally 474.

This method may further include delivering an initial bolus of insulinfollowed by a bolus extension, the bolus extension being delivered overa period of time that is directly proportional to the dose of theinsulin action time modifier 476.

According to another embodiment, the method may further includeidentifying use of an ultra-rapid acting insulin as a factor that islikely to lead to the postprandial drop in blood glucose to a levelbelow a basal level that is likely to deprive the patient of sufficientblood glucose to function normally 478.

According to another embodiment, the method may further includedelivering an initial bolus of insulin followed by a bolus extensiononly if the dose of the agent that slows gastric emptying exceeds apredetermined threshold 480.

Rapid changes in blood glucose level can cause patients with diabetes tofeel uncomfortable or emotionally out of balance in ways that patientsfind hard to describe. This can occur when an excessively large insulinbolus is delivered or if the patient engages in exercise with an excessof insulin in his system. With increasing speed of insulin action it maybe desirable to extend even correction boluses to reduce the rate ofchange of blood sugar level. Thus, according to another embodiment, theinvention includes an alternative insulin delivery protocol wherein acorrection bolus is delivered that includes a correction bolus extensionto moderate the rate at which blood glucose change occurs. According toanother embodiment, the invention includes utilizing an alternativeinsulin delivery protocol that maintains the rate of change of bloodglucose below a preselected level.

The present invention may be embodied in other specific forms withoutdeparting from the spirit of the essential attributes thereof;therefore, the illustrated embodiments should be considered in allrespects as illustrative and not restrictive, reference being made tothe appended claims rather than to the foregoing description to indicatethe scope of the invention.

1. A computer-implemented method of infusing insulin via an insulinpump, comprising: identifying an insulin delivery protocol associatedwith ingestion of carbohydrates wherein the insulin delivery protocol islikely to lead to a postprandial drop in blood glucose to a level belowa basal level that is likely to deprive a patient of sufficient bloodglucose to function normally; and proposing at least one alternativeinsulin delivery protocol to inhibit the postprandial drop in bloodglucose level by delivering a metered amount of insulin that isappropriate to facilitate the metabolism of the carbohydrates withoutthe postprandial blood glucose level drop; and applying the alternativeinsulin delivery protocol.
 2. The computer-implemented method as claimedin claim 1, further comprising applying the alternative insulin deliveryprotocol as follows: delivering a first bolus of the insulin having afirst volume at a time t1; delivering a second bolus of the insulinhaving a second volume at a time t2; delivering a third bolus of theinsulin having a third volume at a time t3.
 3. The computer-implementedmethod as claimed in claim 1, wherein the first volume is less than thesecond volume and the third volume is less than the second volume andtime t1 is followed by time t2 and time t2 is followed by time t3. 4.The computer-implemented method as claimed in claim 1, furthercomprising applying the alternative insulin delivery protocol asfollows: delivering of insulin at a rate based on the expectedpostprandial rise in blood glucose level that approximates the expectedpostprandial rise in blood glucose level, whereby blood glucose ismetabolized such that blood glucose level is maintained to besubstantially constant following the ingestion of carbohydrates.
 5. Thecomputer-implemented method as claimed in claim 1, further comprisingapplying the alternative insulin delivery protocol as follows:delivering insulin at a rate based on the expected postprandial rise inblood glucose level that approximates the expected postprandial rise inblood glucose level such that the rate of infusion as a function of timegenerally resembles a Gaussian curve.
 6. The computer-implemented methodas claimed in claim 5 further comprising identifying the use of a doseof an agent that slows gastric emptying as a factor that is likely tolead to a postprandial drop in blood glucose to a level below a basallevel, and wherein the rate of infusion that generally resembles theGaussian curve is flattened to conform with the slowed rate of gastricemptying.
 7. The computer-implemented method as claimed in claim 6,wherein the agent that slows gastric emptying is selected from a groupof agents consisting of pramlintide, Glucagon Like Peptide-1 agonistsand combinations thereof.
 8. The computer-implemented method as claimedin claim 6, further comprising delivering an initial bolus of insulinfollowed by an insulin bolus extension, the insulin bolus extensionbeing delivered over a period of time that is generally proportional tothe dose of the agent that slows gastric emptying.
 9. Thecomputer-implemented method as claimed in claim 6, further comprisingdelivering an initial bolus of insulin followed by an insulin bolusextension if the dose of the agent that slows gastric emptying exceeds apredetermined threshold.
 10. The computer-implemented method as claimedin claim 1, further comprising receiving an input that the patient hasingested or is about to ingest a quantity of carbohydrate and an inputenumerating the quantity of carbohydrate; and applying the alternativeinsulin delivery protocol if the enumerated quantity of carbohydrateexceeds a predetermined threshold.
 11. The computer-implemented methodas claimed in claim 6, further comprising delivering the dose of theagent that slows gastric emptying via a dual hormone therapy device. 12.The computer implemented method as claimed in claim 1, furthercomprising identifying use of an insulin action time modifier as afactor that is likely to lead to the postprandial drop in blood glucoseto a level below a basal level.
 13. The computer implemented method asclaimed in claim 12, further comprising delivering an initial bolus ofinsulin followed by an insulin bolus extension, the insulin bolusextension being delivered over a period of time that is directlyproportional to the dose of the insulin action time modifier.
 14. Thecomputer implemented method as claimed in claim 1, further comprisingidentifying use of an ultra-rapid acting insulin as a factor that islikely to lead to the postprandial drop in blood glucose to a levelbelow a basal level.
 15. The computer implemented method as claimed inclaim 1, further comprising applying the alternative insulin deliveryprotocol to combine two or more of the following insulin deliveryprotocols a) delivering a first bolus of the insulin having a firstvolume at a time t1; delivering a second bolus of the insulin having asecond volume at a time t2; delivering a third bolus of the insulinhaving a third volume at a time t3: b) delivering a volume of insulin ata rate based on the expecting postprandial rise in blood glucose thatapproximates the expected postprandial rise in blood glucose; c)delivering a insulin at a rate based on the expected postprandial risein blood glucose that approximates the expected postprandial rise inblood glucose whereby blood glucose is metabolized such that the volumerate of infusion generally resembles a Gaussian curve; d) delivering aninitial bolus of insulin followed by a bolus extension, the bolusextension being delivered over a period of time that is directlyproportional to a dose of an agent that slows gastric emptying; e)delivering an initial bolus of insulin followed by a bolus extensiononly if the dose of the agent that slows gastric emptying exceeds apredetermined threshold; f) receiving an input from the patient that thepatient has ingested or is about to ingest a quantity of carbohydrateand an input from the patient enumerating the quantity of carbohydrate;and applying the alternative insulin delivery protocol only if theenumerated quantity of carbohydrate exceeds a predetermined threshold;and g) delivering an initial bolus of insulin followed by a bolusextension, the bolus extension being delivered over a period of timethat is directly proportional to the dose of the insulin action timemodifier.
 16. An automated ambulatory infusion pump for infusing insulininto a living being having a controller, the controller being programmedwith an algorithm that causes the automated ambulatory infusion pump toexecute the following: identifying an insulin delivery protocolassociated with ingestion of carbohydrates wherein the insulin deliveryprotocol is likely to lead to a postprandial drop in blood glucose to alevel below a basal level; proposing at least one alternative insulindelivery protocol to inhibit the postprandial drop in blood glucose bydelivering a metered amount of insulin that is appropriate to facilitatethe metabolism of the carbohydrates without the postprandial bloodglucose drop; and applying the alternative insulin delivery protocol.17. The automated ambulatory infusion pump as claimed in claim 16, thecontroller being further programmed with an algorithm that causes theautomated ambulatory infusion pump to execute the following: identifyingthe use of a dose of an agent that slows gastric emptying as a factorthat is likely to lead to a postprandial drop in blood glucose to alevel below a basal level.
 18. The computer-implemented method asclaimed in claim 17, wherein the agent that slows gastric emptying isselected from a group of agents consisting of pramlintide, Glucagon LikePeptide-1 agonists and combinations thereof.
 19. The automatedambulatory infusion pump as claimed in claim 17, the controller beingfurther programmed with an algorithm that causes the automatedambulatory infusion pump to execute the following: delivering an initialbolus of insulin followed by an insulin bolus extension, the insulinbolus extension being delivered over a period of time that is generallyproportional to the dose of the agent that slows gastric emptying. 20.The automated ambulatory infusion pump as claimed in claim 17, thecontroller being further programmed with an algorithm that causes theautomated ambulatory infusion pump to execute the following: deliveringan initial bolus of insulin followed by an insulin bolus extension onlyif the dose of the agent that slows gastric emptying exceeds apredetermined threshold.
 21. The automated ambulatory infusion pump asclaimed in claim 17, the controller being further programmed with analgorithm that causes the automated ambulatory infusion pump to executethe following: delivering the dose of the agent that slows gastricemptying via a dual hormone therapy device.